Inherently bioactive iron-chelating Poly (N-acryloyl 2-glycine)/chitosan hydrogel scaffolds orchestrating dual hypoxic-immune microenvironment for functional meniscus regeneration

Despite progress in tissue-engineered meniscus (TEM) as alternatives to meniscectomy, challenges remain in inflammatory regulation, oxidative resistance, and mechanical stability under pathological microenvironments. Innovatively, we combined personalized meniscus scaffold, hydrogel ion crosslinking network technology, and microenvironment regulation function to prepare a multifunctional poly (N-acryloyl 2-glycine)/chitosan (PACG/CS) composite hydrogel meniscus scaffold featuring heterogeneous bionic structure, high strength and toughness, hypoxic inducing activity, and anti-inflammatory and antioxidant effects. Crucially, the inherently bioactive hydrogel networks crucially leveraged their carboxyl groups to orchestrate iron ion chelation, establishing a hypoxia-mediated microenvironment that dynamically modulated pro-/anti-inflammatory equilibrium, which in turn supported the chondrocyte survival, facilitated the development of a cartilage matrix, and ultimately promoted the meniscus regeneration. Notably, peripheral blood mesenchymal stem cells (PBMSCs) exhibited superior meniscus regeneration efficiency in low-oxygen conditions compared to bone marrow mesenchymal stem cells (BMSCs). After evaluating the effects of hypoxia environment induced by highly efficient iron chelation of PACG/CS hydrogel scaffolds on the activation of HIF-1α signaling pathway, anti-inflammatory and antioxidant regulation, the regulatory mechanism of immune microenvironment on the growth and cultivation quality of TEM were elucidated <i>in vivo</i> and <i>in vitro</i>. Overall, our have important implications for comprehending the biological impacts of biomaterials and developing novel approaches for meniscus regeneration.